Method for preparing perfluorinated heterocyclic compounds, and compounds prepared by this method

ABSTRACT

A process for the preparation of perfluorinated heterocyclic compounds of the general formulae Ia and Ib 
&lt;IMAGE&gt;
 in which 
 
  m denotes 3 or  4 and 
  X represents a -CF2-O-CF2- group, a -CF2-CF2-CF2- group or a -CF(CF3)-CF2- group, 
 and their mixtures and the perfluoro-N-cyclohexylmorpholine prepared by the process are described. The compounds are obtained by electrochemical perfluorination starting from corresponding cycloalkenyl derivatives and can be employed, inter alia, for the preparation of medicinally utilisable aqueous emulsions such as blood substitutes.

This application is a division of application Ser. No. 07/572,550 filedAug. 27, 1990 and now U.S. Pat. No. 5,091,064

BACKGROUND OF THE INVENTION

The present invention relates to a method for preparing perfluorinated,heterocyclically substituted cycloalkyl compounds and mixtures thereofwith corresponding n-alkyl compounds starting from correspondingunfluorinated cycloalkenyl compounds. The present invention furtherrelates to new perfluorinated compounds prepared for the first time bythe method of the invention, and to the use of these new compounds.

The compounds which can be prepared in accordance with the invention areof the so-called perfluorocarbon type. Perfluorocarbons areperfluorinated organic carbons which are liquid to waxy at roomtemperature under standard pressure. They are water-insoluble,biologically inert compounds which consist of carbon and fluorine, andin some cases may also contain hetero atoms such as nitrogen or oxygen.Such compounds are disclosed, for example, in published European PatentApplication Nos. EP 77,114; EP 99,652; and EP 151,697. Theperfluorocarbon molecules are outstandingly shielded by a uniform shellof fluorine atoms. Therefore, perfluorocarbons are extraordinarily inertchemically and physiologically, and thus nontoxic. Due to theirextremely low intermolecular forces, perfluorocarbons have low boilingpoints in proportion to their molecular weights, and an extraordinarilylow surface tension. The very weak intermolecular forces also areresponsible for the ability of the perfluorocarbons to dissolve largeamounts of gases such as oxygen and carbon dioxide. Due to theseproperties, especially the ability to physically dissolve and transportoxygen, perfluorocarbons have been used in medicine for preparingoxygen-transporting aqueous emulsions of perfluorocarbons, which areused, for example, as blood substitutes or perfusion media. Further,perfluorocarbons are also suitable for use in other technical fields inwhich nontoxic and chemically inert liquid or waxy substances areneeded, or in which inert substances with the ability to dissolve gasesare needed.

Previously known methods for preparing perfluorinated, heterocyclicallysubstituted cycloalkyl compounds start from corresponding saturated,unfluorinated cycloalkyl compounds which must be obtained by complexpreparation methods. In comparison with such processes, the method ofthe invention has the advantage that it uses starting materials whichare easily accessible through a small number of reaction steps.

SUMMARY OF THE INVENTION

The object of the present invention is to develop an economical andimproved method for preparing perfluorinated, heterocyclicallysubstituted cycloalkyl compounds by which new compounds of this typealso are made available.

These and other objects of the invention are achieved by providing amethod for preparing compounds corresponding to the formulas Ia and Ib:##STR2## wherein m is 3 or 4 and X is a --CF₂ --O--CF₂ -- group, a --CF₂--CF₂ --CF₂ -- group or a --CF(CF₃)--CF₂ -- group, or mixtures thereof,said method comprising the steps of:

a) electrolyzing a solution of a compound corresponding to the formulaII: ##STR3## wherein m has the above meaning and A represents oxygen ora --CH₂ -- group, in liquid hydrogen fluoride, and separating a rawreaction product containing perfluorinated compounds of formulas Ia andIb plus partially fluorinated by-products;

b) treating said raw reaction product with an alkali metal or alkalineearth metal base in the presence of water at an elevated temperaturesufficient to decompose the partially fluorinated by-products; and

c) isolating a mixture of the compounds of formulas Ia and Ib from thetreated reaction product from step b).

According to a further aspect of the invention, the objects of theinvention are achieved by providing a perfluoro-N-cyclohexylmorpholineof formula I'a: ##STR4## or a mixture thereof with aperfluoro-N-n-hexylmorpholine of formula I'b: ##STR5##

According to further aspects of the invention, the perfluorocompoundsare separated into isomers using molecular sieves.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

It has been found that perfluorinated, heterocyclically substitutedcycloalkyl compounds and corresponding n-hexyl compounds can be obtainedin good yields by electrochemical fluorination of correspondingunfluorinated, unsaturated cycloalkylene compounds.

The subject of the present invention is a method for preparing compoundsof the general formulas Ia and Ib: ##STR6## wherein m is 3 or 4 and X isa --CF₂ --O--CF₂ -- group, a --CF₂ --CF₂ --CF₂ -- group or a--CF(CF₃)--CF₂ -- group, or mixtures thereof, characterized in that

a solution of compounds of the general formula II ##STR7## wherein m hasthe above meaning and A represents oxygen or a --CH₂ -- group, iselectrolyzed in liquid hydrogen fluoride, and a raw reaction productcontaining the perfluorinated compounds of formulas Ia and Ib plus onlypartially fluorinated by-products is separated;

b) the raw reaction product is treated with an alkali metal or alkalineearth metal base, especially an alkali metal or alkaline earth metalhydroxide, in the presence of water and, optionally, a lower aliphaticprimary or secondary amine at an elevated temperature sufficient todecompose only partially fluorinated by-products;

c) a mixture of the compounds of formulas Ia and Ib is isolated from areaction mixture obtained in process step b), and this is separated, ifdesired, into the compounds of formulas Ia and Ib, and

d) if desired, isomer mixtures of compounds Ia or Ib, wherein X is a--CF₂ --CF₂ --CF₂ -- group and m has the above meaning, and compounds offormulas Ia or Ib which are isomeric therewith, wherein X represents a--CF(CF₃)--CF₂ -- group, are separated into the individual isomers.

It is considered surprising that compounds of formula II can be reactedto produce corresponding mixtures of perfluorinated compounds offormulas Ia and Ib without cleaving the molecule at the double bond andforming cleavage products and/or polymeric derivatives thereof.

The invention also includes the new perfluoro-N-cyclohexylmorpholine offormula I'a, which has been prepared for the first time, and mixturesthereof with perfluoro-N-n-hexylmorpholine of formula I'b: ##STR8##

Due to their chemical and physiological inertness and their ability todissolve gases such as oxygen and carbon dioxide, the perfluorinatedheterocyclic compounds prepared according to the invention are usablefor the same uses as mentioned above for perfluorocarbons.

The compound of formula I'a is characterized by an especially desirableprofile of properties, on the basis of which it and its mixtures withcompound I'b are especially suitable for preparing aqueousperfluorocarbon emulsions capable of transporting oxygen, which can beused in medicine, for example as blood substitutes or also for perfusionand storage of organs in transplant surgery.

Perfluorocarbons are hydrophobic, water-immiscible substances.Therefore, they cannot be introduced as such into the circulatorysystem, but only in the form of physiologically acceptable aqueousemulsions. Such emulsions are prepared conventionally by using aphysiologically acceptable emulsifier and constitute oil-in-water typeemulsions.

In addition to good physiological compatibility, e.g., osmotic andoncotic (colloid osmotic) pressures, rheological properties and pHconstancy similar to those of normal blood, and a good capacity fordissolving oxygen, it is important for emulsions usable as bloodsubstitutes that they have an appropriate residence time in thecirculatory system, and subsequently are eliminated as completely aspossible and without excessive retention in organs. Half-lives in thebody of about one week to one month, especially of about two to fourweeks, are considered advantageous. Also it is important that theemulsions have sufficient stability against growth of the oil phaseparticles.

Due to their chemical inertness, perfluorocarbons are virtually notmetabolized at all in the body and are excreted unchanged in the breathor through the skin. The rate of excretion of individualperfluorocarbons differs greatly and can vary from a few days to severalyears. The rate of excretion of the individual substances dependsgreatly on their vapor pressure and on their solubility in slightlypolar media, since the rate of permeation of the perfluorocarbonsthrough the alveolar membranes depends on these parameters.

The critical temperature of dissolution in n-hexane (=CTSH) can serve asa measure of the lipophilia of the perfluorocarbons, that is, thetemperature at which the particular perfluorocarbon dissolves in anequal amount of n-hexane. The determination of the CTSH of aperfluorocarbon is therefore an in vitro test method which represents agood index of the retention time of the perfluorocarbon in the body. Anadequate lipophilia and a sufficiently high vapor pressure areadvantageous for a satisfactory exhalation rate.

The compound of formula Ia' is especially suited as an oxygen carryingcomponent of perfluorocarbon emulsions suitable as blood substitutes,since in addition to a high capacity for dissolving oxygen, it has bothgood emulsifiability and a CTSH and vapor pressure favorable to a goodhalf-life in the body with a good rate of elimination.

In accordance with the invention, mixtures of compounds of formula Iaand the by-products of formula Ib are prepared by electrochemicalfluorination of unsaturated compounds of formula II by electrolyzingsolutions of the compounds of formula II in liquid hydrogen fluoride.Advantageously, solutions of 4 to 30 wt.-%, preferably 5 to 10 wt.-%, ofa compound of formula II in liquid hydrogen fluoride are used for theprocess. The electrolysis advantageously takes place in an electrolysiscell at temperatures between -25° and +10° C. preferably between -5° and+5° C.; at an anode current density of 2-30 mA/cm² and a cell voltage of3-10, especially 4-8 volts. For the electrolysis it may prove helpful tofeed the electrolyte to the vicinity of the electrodes again and againby continuously stirring the contents of the cell.

Since electrochemical fluorination in liquid hydrogen fluoride is a veryhigh-energy process, in which the perfluorination often is associatedwith considerable side reactions, it was not to be expected thatunsaturated bicyclic compounds of formula II could be perfluorinated byelectrochemical fluorination with a yield sufficient for the practicalproduction of compounds Ia. Rather, it would have been expected forcleavage at the C═C double bonds of the cycloalkylene ring and also thecleavage of carbon-to-hetero atom bonds to occur. Electrochemicalperfluorination of the compounds of formula II is successful inaccordance with the invention, with satisfactory yields, if it isperformed in the above-stated, relatively low temperature range and atthe above-stated relatively low cell voltage.

For further processing, the raw reaction product which settles as aheavy phase on the bottom of the electrolysis cell is separated and, todecompose any only partially fluorinated by-products, it is subjected totreatment with an alkali metal or alkaline earth metal hydroxide, in thepresence of water and, optionally, a lower aliphatic primary orsecondary amine, at a temperature sufficiently high to decompose anypartially fluorinated by-products. This process step can be performedunder known reaction conditions, for example, in a manner analogous tothe methods described in published European Patent Application Nos. EP99,652 and EP 151,697. It has proved advantageous to treat the rawreaction product with a 6N to 10N aqueous alkali metal hydroxidesolution, especially potassium hydroxide solution, and a lower aliphaticamine at elevated temperature, preferably the boiling temperature of thereaction mixture. Thus, the reaction mixture can be heated to boilingwith refluxing for a period of from several hours up to 8 days. Suitablelower aliphatic amines are lower primary or secondary amines or diamineswhich are liquid at room temperature, preferably secondary amines suchas, for example, dialkylamines with up to 5 carbon atoms in their alkylmoieties, or hexamethylene diamine or also cyclic amines such aspiperidine. Preferably a dibutyl amine, such as, for example, diisobutylamine, is used.

From the resultant reaction mixture, mixtures of compounds of formula Iaand Ib can be isolated in a known manner, for example by fractionaldistillation. The mixtures, in which the compounds of formula Iagenerally predominate, can be separated in a known manner, if desired,into the compounds of formulas Ia and Ib.

The mixtures separated from the reaction mixture by fractionaldistillation are free from any non-perfluorinated products. However,they may contain, in addition to the principal product of formula Ia,some likewise perfluorinated, and therefore chemically andphysiologically inert, by-products. In particular, they may containperfluorinated by-products which have a molecular weight similar to thatof the principal product and therefore boil in the same temperaturerange as the principal product. The presence of such perfluorinatedby-products, however, does not impair the proper use of the compounds,so that the products purified by distillation can generally be usedwithout further purification.

Under the conditions of the electrochemical perfluorination of compoundsof formula II, a ring contraction occurs to some extent in compoundscontaining piperidine rings, so that in addition to compounds offormulas Ia and Ib, in which X represents a --CF₂ --CF₂ --CF₂ -- group,compounds isomeric therewith, in which X represents a --CF(CF₃)--CF₂ --group, are obtained to a lesser extent. These isomer mixtures ofcompounds of formula Ia and/or Ib can be used in the same manner as purecompounds of formulas Ia and/or Ib.

If desired, the isomer mixtures can be separated into their individualisomers. It is desirable to perform a separation of mixtures ofcompounds Ia and Ib and/or a separation of isomers byadsorption/desorption on molecular sieves, preferably molecular sieveswith a pore size of 5 to 6 Å. Suitable molecular sieves include, forexample, inorganic aluminosilicates, zeolites and silicalites (=silicondioxide with a suitable pore size). Zeolites are preferably used.Inorganic molecular sieves are generally suitable for separatingcompounds containing only unsubstituted perfluorinated rings fromby-products containing perfluoroalkyl substituents. Depending on thesize of the perfluoroalkyl substituents, molecular sieves with poresizes between 5 and 6.5 Å are selected for this purpose. Isomer mixturescan also be separated in a known manner by preparative gaschromatography.

The starting compounds of formula II are known, or they can be preparedby known methods or in a manner analogous to known methods.

The compounds prepared in accordance with the invention, especiallycompound I'a or its mixtures with compound I'b can be made in a knownmanner into medically usable aqueous emulsions. Such emulsions areoil-in-water type emulsions which contain 5 to 50, especially 15 to 25,preferably about 20, grams of perfluorinated compounds, i.e. compoundsof formula Ia or Ib or their mixtures, and optionally otherphysiologically acceptable perfluorocarbons, per 100 milliliters ofemulsion, and a physiologically acceptable emulsifier, optionallyfurther physiologically acceptable adjuvants. It may be desirable to useperfluorocarbon mixtures which contain a small proportion of relativelyhigh-boiling compounds.

Physiologically acceptable emulsifiers which are themselves nontoxic,have no hemolysis-causing properties, and otherwise do not have anyinteraction with components of natural blood and which are completelyeliminated from the body or metabolized to nontoxic metabolites, aresuitable for use as the emulsifiers. Suitable emulsifiers include, forexample, natural phospholipids such as egg lecithins or soya lecithins,and albumins. Also suitable are physiologically acceptable, nonionicemulsifiers of the ethylene oxide-propylene oxide copolymer type, e.g.,copolymers with a molecular weight in the range from 8000 to 8500. Suchemulsifiers are commercially available, for example under the trademarkPluronic™, from Wyandotte Chemicals Corp. The emulsifiers can becontained in the emulsions in accordance with the invention in accncentration of, for example, 2 to 7 grams per 100 milliliters ofemulsion. Also, the emulsions can contain additional adjuvants andadditives commonly used in blood substitutes, such as salts andsubstances which serve to establish a physiologically acceptable pHvalue and/or osmotic and oncotic pressure.

The emulsions can be prepared in a known manner by conventionalemulsifying techniques. For example, emulsification may be performed byultrasonic and/or high-pressure homogenization.

The emulsions may be used in medicine as oxygen transporting bloodsubstitutes. Also, they are usable as oxygen carrying perfusionsolutions, for example for protecting exposed organs in surgery, such asprotecting the myocardium against hypoxia in heart surgery. Theemulsions can furthermore be used as adjuvants in diagnostics, forexample for ultrasonography and ¹⁹ F NMR tomography. In biotechnology,such emulsions can be used in oxygen carrying nutrients, for example forcultivating animal and plant cells or in the synthesis of interferon.

The compounds of formula Ia or Ib or their mixtures can also be used inother fields of technology, in which liquid or waxy substances areneeded which are chemically inert and/or have a capacity for dissolvinggases. The compounds and mixtures are suitable, for example, as inertcoolants, lubricants, sealing fluids and hydraulic fluids, insulationmedia in electrical engineering, and means for vapor phase soldering oras additives in agents for the above-named purposes. Because of theircapacity for dissolving gases, the compounds and their mixtures aresuitable as an inert medium for the diffusion of gases between differentphases. Thus the compounds can also be used in processes for thetechnical separation of gases, such as the separation of gases bydialysis, in which the compounds serve as the inert exchange phase.

The following examples are intended to further explain the inventionwithout, however, limiting its scope.

As electrolysis cells for the electrochemical fluorination, cells withnickel electrodes are used which have either a capacity of 300 ml and ananode surface area of 475 cm², or a capacity of 960 ml and an anodesurface area of 1530 cm². The cells are provided with a reflux condenserwhich is maintained at a temperature between -15° and -20° C.

EXAMPLE 1 Preparation of a mixture of perfluorocyclohexylmorpholine andperfluoro-n-hexylmorpholine.

A 5% to 15% solution of morpholinecyclohexene-(1) in pre-dried,refrigerated liquid hydrogen fluoride was perfluorinated in anelectrolysis cell at an anode current density of 3 to 20 mA/cm², a cellvoltage of 5 to 6.5 volts and a cell temperature of -8° to +5° C. Fromtime to time additional morpholinocyclohexene-(1) dissolved in liquidhydrogen fluoride was added and spent hydrogen fluoride replaced toenable the cell to be operated continuously. The heavy phase containingthe raw reaction product, which settled on the cell bottom, waswithdrawn from time to time. The raw product was treated with equalvolumes of an aqueous 8N potassium hydroxide solution and dibutylamine.The mixture was heated at reflux for 8 days. Then the mixture wasfractionally distilled. In the distillation a main fraction was obtainedin the boiling range of 145° to 148° C., which consisted primarily ofperfluorinated cyclohexylmorpholine and can be used without furtherpurification for most of the applications referred to in the abovedescription. The yield was 30%. Gas chromatographic analysis showed thatthe distillate was a mixture of 65% of the principal product,perfluorocyclohexyl morpholine, 33% of the by-product,perfluoro-n-hexylmorpholine, and 2% additional by-products, with aboiling point of 147.5°-148.5° C. and a vapor pressure of 12 torr at 37°C.

EXAMPLE 2 Preparation of a mixture of perfluorocyclohexylmorpholine andperfluoro-n-hexylmorpholine.

The procedure described in Example 1 was followed, but an electrolysiscell was used which was additionally provided with a circulating pump.By constantly recirculating the entire cell contents, the electrolytewas fed again and again into the electrode area during the electrolysis.For continuous operation, additional starting product was supplied fromtime to time as described in Example 1. The electrolysis process wasfollowed by monitoring the changes in current and voltage. From time totime, whenever a sharp drop in conductivity indicated an increase in theconcentration of perfluorinated product and a corresponding decrease inthe electrolyte concentration, the circulation was interrupted and theheavy phase containing the raw product which collected on the bottom ofthe cell was withdrawn. The raw product was worked up as described inExample 1. The mixture obtained as distillate had the composition givenin Example 1. A yield of 43% was achieved.

EXAMPLE 3

Preparation of pure perfluorocyclohexylmorpholine by separating themixtures obtained in Examples 1 or 2.

The mixture of perfluorocyclohexylmorpholine andperfluoro-n-hexylmorpholine obtained in Example 1 was introduced at 120°C. through an evaporator to a glass column filled with a zeolitemolecular sieve having a pore size of 5 Å through which a constantstream of helium flowed at a rate of 60 ml per minute. While theperfluorocyclohexylmorpholine passed through the column, the by-productcontaining the C₆ F₁₃ moiety was largely retained. Thus, pureperfluorinated cyclohexylmorpholine was obtained with a boiling point of147.5°-149.5° C. After all of the perfluorocyclohexylmorpholine andexcess perfluoro-n-hexylmorpholine had left the column, the temperaturewas increased to 300° C. In a refrigerated trap at the column outletpure perfluoro-n-hexylmorpholine condensed, having a boiling point of149°-150° C.

The perfluorocyclohexylmorpholine and the perfluoro-n-hexylmorpholinehad a vapor pressure of 12 torr at 37° C.

The oxygen dissolving capacity (=O₂ solv.) of theperfluorocyclohexylmorpholine and the perfluoro-n-hexylmorpholine, andtheir critical temperature of solution in n-hexane (=CTSH), which can beconsidered as a good index for the residince time of theperfluorocarbons in the body, were determined by the following methods:

A. Determination of the oxygen dissolving capacity.

The determination was performed in a two-liter round flask provided witha valve for delivery of oxygen, a valve for evacuation, and a pressuregauge, and with a bottom extension suitable for containing theperfluorocarbon, into which the perfluorocarbon can be introducedthrough a septum.

The apparatus was first evacuated with a water-jet pump, filled withoxygen, evacuated again, and again filled with oxygen until an internalpressure of 1013 mbar was reached. Then the perfluorocarbon wasintroduced through a septum into the bottom extension and stirred therefor 2 hours under an oxygen atmosphere. The temperature was maintainedat 37° C. by means of a cryostat. After 2 hours part of theperfluorocarbon was removed and tested by gas chromatography for itsoxygen content.

The gas chromatographic investigation was performed with a CAP 12 gaschromatograph made by Gira, France. The carrier gas was helium with aflow rate of 20 ml/min. The separating column was a glass columnmeasuring 2 m×4 mm diameter, filled with a 5 Å molecular sieve of 40-60mesh. The oven temperature was 100° C.; the injector temperature 250°C., and the detector temperature 200° C. The sample volume was 30 to 50μl.

B. Determination of the critical temperature of dissolution in n-hexane.

Equal volumes (50 μl each) of the perfluorocarbon and n-hexane weremelted into a glass tube (about 3 cm long, diam. 3 mm) with cooling(-70° C.). To determine the miscibility of the two liquids, the bathtemperature in an apparatus for determining melting points was slowlyraised and lowered, and the temperature at which the two phases mix orbecome visible was measured.

    ______________________________________                                        Results:           O.sub.2 solv. @ 37° C.                                                              CTSH                                          ______________________________________                                        Perfluorocyclohexylmorpholine                                                                    47 vol %     32° C.                                 Perfluoro-n-hexylmorpholine                                                                      45 vol %     45° C.                                 ______________________________________                                    

The foregoing results show that the compounds are suitable for use asoxygen carrying perfluorocarbons, and that perfluorocyclohexylmorpholinehas a substantially lower CTSH than perfluoro-n-hexylmorpholine. This isan indication of a half-life in the body that is well suited for use inblood substitutes.

Analogously to the methods described in the foregoing examples,perfluorocyclopentylmorpholine orperfluorocyclopentylmorpholine/perfluoro-n-pentylmorpholine mixtures,and perfluorocyclohexylpiperidine orperfluorocyclohexylpiperidine/perfluoro-n-hexylpiperidine mixtures, canalso be obtained in good yields, of over 40% for example, byelectrochemical perfluorination of corresponding starting compounds offormula II. The starting compounds of formula II can be prepared in amanner analogous to the procedure given below for preparingmorpholinocyclohexene-(1).

Preparation of morpholinocyclohexene-(1)

1.2 mol of morpholine is heated with 1.0 mole cyclohexanone and 200 mltoluene on the water separator until no more water of reaction isseparated. Then the compound of formula II is isolated from the reactionmixture by fractional distillation.

EXAMPLE I Preparation of an aqueous emulsion containing a perfluorinatedcyclohexylmorpholine.

2 g of the perfluorinated cyclohexylmorpholine obtained in Example 2 wasadded to 0.3 g of the emulsifier, Pluronic® F68 (=ethyleneoxide-propylene oxide block polymer, average molecular weight 8300; fromWyandotte Chemical) and water was added to the mixture to make the totalvolume 10 ml. It was homogenized for 2 minutes with ultrasound. Theresulting emulsion had a colloidal particle size of approximately 200nm, which remained constant upon standing at +4° C. for several weeks.

EXAMPLE II

Aqueous emulsion containing perfluorinated cyclohexylmorpholine suitableas a blood substitute or perfusion medium.

    ______________________________________                                        Composition:                                                                  ______________________________________                                        Perfluorinated cyclohexylmorpholine                                                                200        g/l                                           obtained according to Example 2                                               Emulsifier (Pluronic ® F68)                                                                    27         g/l                                           Glycerin             8          g/l                                           Egg white phospholipids                                                                            4          g/l                                           Hydroxyethyl starch (average                                                  molecular weight 200,000)                                                                          30         g/l                                           Na+                  128.0      mmol/l                                        K+                   4.5        mmol/l                                        Ca++                 2.5        mmol/l                                        Mg++                 2.1        mmol/l                                        Cl-                  116.0      mmol/l                                        HCO.sub.3 -          25         mmol/l                                        Glucose              10.0       mmol/l                                        Sterile distilled water                                                                            to make 1  liter                                         ______________________________________                                    

The listed components were homogenized in a known manner.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, thescope of the invention should be construed to include all modificationsfalling within the ambit of the appended claims and equivalents thereof.

What is claimed is:
 1. An aqueous perfluorocarbon oil-in-water emulsionsuitable for use as an oxygen carrying blood substitute comprising waterand an oxygen carrying agent selected from the group consisting ofperfluoro-N-cyclohexylmorpholine of Formula I'a: ##STR9## and a mixtureof perfluoro-N-cyclohexylmorpholine of Formula I'a withperfluoro-N-n-hexylmorpholine of Formula I'b: ##STR10##
 2. A mixture ofperfluoro-N-cyclohexylmorpholine of formula I'a: ##STR11## withperfluoro-N-n-hexylmorpholine of formula I'b: ##STR12##
 3. In a methodof blood replacement comprising introducing into the circulatory systemof a mammal an oxygen transport medium comprising a physiologicallyacceptable, aqueous emulsion of a perfluorocarbon, the improvementcomprising using as said perfluorocarbon aperfluoro-N-cyclohexylmorpholine of formula I'a: ##STR13## or a mixtureof said perfluoro-N-cyclohexylmorpholine of formula I'a withperfluoro-N-n-hexylmorpholine of formula I'b: ##STR14##
 4. A methodaccording to claim 3, wherein said perfluorocarbon isperfluoro-N-cyclohexylmorpholine of formula I'a.
 5. A method accordingto claim 3, wherein said perfluorocarbon is a mixture ofperfluoro-N-cyclohexylmorpholine of formula I'a andperfluoro-N-n-hexylmorpholine of formula I'b.
 6. In a method ofperfusing or storing organs comprising immersing said organ in anoxygen-containing solution comprising an aqueous emulsion of aperfluorocarbon, the improvement comprising using as saidperfluorocarbon a perfluoro-N-cyclohexylmorpholine of formula I'a:##STR15## or a mixture of said perfluoro-N-cyclohexylmorpholine offormula I'a with perfluoro-N-n-hexylmorpholine of formula I'b: ##STR16##7. A method according to claim 6, wherein said perfluorocarbon isperfluoro-N-cyclohexylmorpholine of formula I'a.
 8. A method accordingto claim 6, wherein said perfluorocarbon is a mixture ofperfluoro-N-cyclohexylmorpholine of formula I'a andperfluoro-N-n-hexylmorpholine of formula I'b.